Chemistry:Flumequine

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Short description: Chemical compound
Flumequine
Flumequine.svg
Clinical data
Other names9-Fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid
AHFS/Drugs.comInternational Drug Names
ATC code
Legal status
Legal status
  • removed from clinical use
Pharmacokinetic data
Excretionurine and feces
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC14H12FNO3
Molar mass261.252 g·mol−1
3D model (JSmol)
Melting point253 to 255 °C (487 to 491 °F)
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Flumequine[1] is a synthetic fluoroquinolone antibiotic[2][3] used to treat bacterial infections. It is a first-generation fluoroquinolone antibacterial that has been removed from clinical use and is no longer being marketed.[4] The marketing authorization of flumequine has been suspended throughout the EU.[5] It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Flumequine was used in veterinarian medicine for the treatment of enteric infections (all infections of the intestinal tract),[6] as well as to treat cattle, swine, chickens, and fish, but only in a limited number of countries.[4][7][8] It was occasionally used in France (and a few other European Countries) to treat urinary tract infections under the trade name Apurone.[4][9] However this was a limited indication[10] because only minimal serum levels were achieved.[11]

History

The first quinolone used was nalidixic acid (was marketed in many countries as Negram) followed by the fluoroquinolone flumequine.[4] The first-generation fluoroquinolone agents, such as flumequine, had poor distribution into the body tissues and limited activity. As such they were used mainly for treatment of urinary tract infections. Flumequine (benzo quinolizine) was first patented in 1973, (German Patent) by Rikker Labs.[12] Flumequine is a known antimicrobial compound described and claimed in U.S. Pat. No. 3,896,131 (Example 3), July 22, 1975.[13] Flumequine is the first quinolone compound with a fluorine atom at the C6-position of the related quinolone basic molecular structure.[14] Even though this was the first fluoroquinolone, it is often overlooked when classifying the drugs within this class by generations and excluded from such a list.

Though used frequently to treat farm animals and on occasion household pets, flumequine was also used to treat urinary tract infections in humans. Flumequine, was used transiently treat urinary infections[9] until ocular toxicity was reported.[15][16][17] as well as liver damage[18] and anaphylactic shock.[19][20]

In 2008, the United States Food and Drug Administration (FDA) requested that all quinolone/fluoroquinolone drugs package inserts include a Black Boxed Warning concerning the risk of spontaneous tendon ruptures, which would have included flumequine. The FDA also requested that the manufacturers send out Dear Doctor Letters regarding this new warning. Such tendon problems have also been associated with flumequine.[21]

Drug residue

The use of flumequine in food animals had sparked considerable debate. Significant and harmful residues of quinolones have been found in animals treated with quinolones and later slaughtered and sold as food products. There has been significant concern regarding the amount of flumequine residue found within food animals such as fish, poultry and cattle.[22][23] In 2003 the Joint FAO/WHO Committee on Food Additives (JECFA) withdrew the maximum residue limits (MRLs) for flumequine and carbadox based on evidence showing both are direct acting genotoxic carcinogens, therefore the Committee was unable to establish an Acceptable Daily Intake (ADI) for human exposure to such residues.[24] Subsequently, in 2006, the JEFCA, re-established the ADI having received appropriate evidence and MRLs were re-specified. The role of JECFA is to evaluate toxicology, residue chemistry and related information and make recommendations for acceptable daily intake (ADI) levels and maximum residue limits (MRLs). At its 16th session, held May 2006, the Committee on Residues of Veterinary Drugs in Foods (CCRVDF) requested information on registered uses of flumequine. As the CCRVDF did not receive any information regarding the registered uses of flumequine that they had requested, the committee members agreed to discontinue work on the MRLs for flumequine in shrimp.[25][26]

Licensed uses

Urinary tract infections (veterinary and human)[27]

Availability

Veterinary use:

  • Solution; Oral; 20% (prescription only)
  • Solution; Oral; 10% (prescription only)

Human use:

  • Tablet; Oral; Flumequine 400 mg (discontinued)

Mode of action

Flumequine is a member of the quinolone antibiotics family, which are active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[28] enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine),[29] display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.[30]

Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.).[31]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[32][33][34][35]

As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[36][37][38][39][40][41]

There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.[30][42]

Adverse reactions

Flumequine was associated with severe ocular toxicity, which precluded its use in human patients.[15][16][17] Drug-induced calculi (kidney stones) has been associated with such therapy as well.[43][44][45] Anaphylactic shock induced by flumequine therapy has also been associated with its use.[19][20][46] Anaphylactoid reactions such as shock, urticaria, and Quincke’s oedema have been reported to generally appear within two hours after taking the first tablet. There were eighteen reports listed within the WHO file in 1996.[47] As with all drugs within this class, flumequine therapy may result in severe central nervous system (CNS) reactions,[48][49][50] phototoxicity resulting in skin reactions like erythema, pruritus, urticaria and severe rashes,[51][52] gastrointestinal and neurological disorders.[9]

Drug interactions

Flumequine was found to have no effect on theophylline pharmacokinetics.[53]

Chemistry

Flumequine is a 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The molecular formula is C14H12FNO3. It is a white powder, odorless, flavorless, insoluble in water but soluble in organic solvent.[54]

Pharmacokinetics

Flumequine is considered to be well absorbed and is excreted in the urine and feces as the glucuronide conjugates of the parent drug and 7-hydroxyflumequine. It is eliminated within 168 hours post-dosing. However, studies concerning the calf liver showed additional unidentified residues, of which a new metabolite, ml, represented the major single metabolite 24 hours after the last dose and at all subsequent time points. The metabolite ml, which exhibited no antimicrobial activity, was present in both free and protein-bound fractions. The major residue found in the edible tissues of sheep, pigs, and chickens was parent drug together with minor amounts of the 7-hydroxy-metabolite. The only detected residue in trout was the parent drug.[55]

See also

  • Adverse effects of fluoroquinolones

References

  1. ↑ INN: Lomefloxacin Hydrochloride
  2. ↑ "Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story". Clinical Infectious Diseases 44 (7): 977–980. April 2007. doi:10.1086/512369. PMID 17342653. 
  3. ↑ "[Chemotherapeutic agents under study]" (in ja). Nihon Rinsho. Japanese Journal of Clinical Medicine 56 (12): 3096–3099. December 1998. PMID 9883617. 
  4. ↑ 4.0 4.1 4.2 4.3 "Quinolones and fluoroquinolones". Pharmacorama. http://www.pharmacorama.com/en/Sections/Nucleic-acids-7.php. 
  5. ↑ "Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics". 11 March 2019. https://www.ema.europa.eu/en/medicines/human/referrals/quinolone-fluoroquinolone-containing-medicinal-products. 
  6. ↑ "Flumequine". Joint FAO/WHO Expert Committee on Food Additives. Residues of some veterinary drugs in animals and foods.. Rome: Food and Agriculture Organization. 1998. ISBN 92-5-104128-8. OCLC 39798999. 
  7. ↑ "Use of quinolones in food animals and potential impact on human health". WHO meeting. Geneva, Switzerland: World Health Organization. June 1998. https://www.fda.gov/ohrms/dockets/dailys/03/Aug03/081403/03n-0324-bkg0001-10-tab7-vol2.pdf.  Cattle only in Europe and Latin America. (Limited use in Latin America), Poultry only in Europe, Asia and Latin America, Fish only in Asia
  8. ↑ "IX4Q 4586, Brrytrit 3.23% Concentrate Solution for Use in Chicken Drinking Water, Genera. Correspondence, Published Literure". Bayer. https://www.fda.gov/ohrms/dockets/dailys/02/Jan02/011102/00n-1571_c000191_06_Exhibit_05_vol25.pdf. "Quinalones are often used to treat severe cases of human infection with Campylobacter spp., and they are also used in veterinary medicine, especially for treating poultry." 
  9. ↑ 9.0 9.1 9.2 "A multicentre study of flumequine in the treatment of urinary tract infections". The Journal of Antimicrobial Chemotherapy 21 (1): 101–106. January 1988. doi:10.1093/jac/21.1.101. PMID 3356617. 
  10. ↑ The quinolones (Third Edition 2000) By Vincent T. Andriole Chapter I History and overview By Dr. Peter Ball (page 5)
  11. ↑ "New classification and update on the quinolone antibiotics". American Family Physician 61 (9): 2741–2748. May 2000. PMID 10821154. 
  12. ↑ "Generics (UK) Ltd v Daiichi Pharmaceutical Co Ltd". Reports of Patent, Design and Trade Mark Cases 126 (2): 102. 2009. doi:10.1093/rpc/rcn037. 
  13. ↑ "Substituted benzo(ij)quinolizine-2-carboxylic acids and derivatives thereof - Patent 3896131". Freepatentsonline.com. http://www.freepatentsonline.com/3896131.html. 
  14. ↑ "[The history of the development and changes of quinolone antibacterial agents]" (in ja). Yakushigaku Zasshi 38 (2): 161–179. 2003. PMID 15143768. 
  15. ↑ 15.0 15.1 "[Serous macular detachment and treatment with flumequine (Apurone = urinary antibacterial). Apropos of 2 cases]" (in fr). Bulletin des Societes d'Ophtalmologie de France 83 (8–9): 1019–1021. 1983. PMID 6378414. 
  16. ↑ 16.0 16.1 "[Ocular side effects of flumequine. 3 cases of macular involvement]" (in fr). Therapie 39 (5): 595–600. 1984. PMID 6506018. 
  17. ↑ 17.0 17.1 "Quinolone generations: natural history or natural selection?". The Journal of Antimicrobial Chemotherapy 46 (Suppl T1): 17–24. July 2000. doi:10.1093/oxfordjournals.jac.a020889. PMID 10997595. 
  18. ↑ "[Immunoallergic hepatitis induced by flumequine]" (in fr). Gastroenterologie Clinique et Biologique 7 (2): 217–218. February 1983. PMID 6840466. 
  19. ↑ 19.0 19.1 "[Anaphylactic shock induced by flumequine]" (in fr). Therapie 47 (5): 440. 1992. PMID 1299991. 
  20. ↑ 20.0 20.1 "[A case of anaphylactic shock induced by flumequine]" (in fr). Presse Médicale 14 (32): 1712. September 1985. PMID 2932732. 
  21. ↑ "Fluoroquinolones- A Review– Dr.T R RAMANUJAM.M.D". Medindia.net. http://www.medindia.net/articles/flouroquinolones_print.htm. 
  22. ↑ "Confirmation of Oxolinic Acid and Flumequine Residues in Shrimp by Liquid Chromatography with Tandem Mass Spectrometry Detection". FDA Science. April 27–28, 2005. http://www.accessdata.fda.gov/scripts/oc/scienceforum/sf2005/Search/preview.cfm?abstract_id=429&backto=category. 
  23. ↑ "Chemotherapeutics in Seafood Compliance Program: Chapter 4: Pesticides and Chemical Contaminants". Compliance Program Guidance Manual. U.S. Food and Drug Administration. https://www.fda.gov/downloads/Food/GuidanceComplianceRegulatoryInformation/ComplianceEnforcement/ucm073192.pdf. "Residue found in Catfish/Basa, Shrimp, salmon, trout" 
  24. ↑ "FAO/WHO Expert Committee on Food Additives, Geneva, Switzerland". Fda.gov. 2009-10-28. https://www.fda.gov/AnimalVeterinary/NewsEvents/FDAVeterinarianNewsletter/ucm100276.htm. 
  25. ↑ "FDA Veterinarian Newsletter, Volume XXII, No. V, 2007". https://www.fda.gov/downloads/AnimalVeterinary/NewsEvents/FDAVeterinarianNewsletter/UCM055721.pdf. 
  26. ↑ "Codex Committee on Veterinary Drug Residues Acts on Several Documents at 17th Session". Fda.gov. 2009-10-28. https://www.fda.gov/AnimalVeterinary/NewsEvents/FDAVeterinarianNewsletter/ucm109981.htm. 
  27. ↑ WHO Drug Information Vol. 2, No. 3, 1988
  28. ↑ "DNA gyrase, topoisomerase IV, and the 4-quinolones". Microbiology and Molecular Biology Reviews 61 (3): 377–392. September 1997. doi:10.1128/mmbr.61.3.377-392.1997. PMID 9293187. 
  29. ↑ "Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group". Antimicrobial Agents and Chemotherapy 36 (4): 751–756. April 1992. doi:10.1128/aac.36.4.751. PMID 1323952. 
  30. ↑ 30.0 30.1 "The quinolone family: from antibacterial to anticancer agents". Current Medicinal Chemistry. Anti-Cancer Agents 3 (6): 439–450. November 2003. doi:10.2174/1568011033482279. PMID 14529452. "The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models". 
  31. ↑ "Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts". Antimicrobial Agents and Chemotherapy 29 (6): 1073–1078. June 1986. doi:10.1128/AAC.29.6.1073. PMID 3015015. 
  32. ↑ "Mutagenicity of Norfloxacin and AM-833 in Bacteria and Mammalian Cells". Reviews of Infectious Diseases 10 (Supplement 1): S148–9. 1988. 
  33. ↑ "Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth". Antimicrobial Agents and Chemotherapy 31 (5): 774–779. May 1987. doi:10.1128/AAC.31.5.774. PMID 3606077. 
  34. ↑ "Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems". Antimicrobial Agents and Chemotherapy 34 (1): 8–12. January 1990. doi:10.1128/AAC.34.1.8. PMID 2158274. 
  35. ↑ "4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells". Journal of Cellular Biochemistry 51 (2): 165–174. February 1993. doi:10.1002/jcb.240510208. PMID 8440750. 
  36. ↑ "Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast". The Journal of Biological Chemistry 267 (19): 13150–13153. July 1992. doi:10.1016/S0021-9258(18)42185-0. PMID 1320012. 
  37. ↑ "Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity". Journal of Medicinal Chemistry 35 (25): 4745–4750. December 1992. doi:10.1021/jm00103a013. PMID 1469702. 
  38. ↑ "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutation Research 425 (2): 213–224. April 1999. doi:10.1016/S0027-5107(99)00044-5. PMID 10216214. 
  39. ↑ "Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicological Sciences 69 (2): 317–321. October 2002. doi:10.1093/toxsci/69.2.317. PMID 12377980. 
  40. ↑ "Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in Escherichia coli". The Journal of Antimicrobial Chemotherapy 25 (5): 733–744. May 1990. doi:10.1093/jac/25.5.733. PMID 2165050. 
  41. ↑ "Fluoroquinolones and Quinolones". The American Academy of Optometry (British Chapter). http://www.academy.org.uk/pharmacy/fluoroq.htm. 
  42. ↑ "A new class of dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole, oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". Journal of the Brazilian Chemical Society 14 (5): 790–796. 2003. doi:10.1590/S0103-50532003000500014. 
  43. ↑ "[Detection and diagnosis of drug induced lithiasis]" (in fr). Annales de Biologie Clinique 41 (4): 239–249. 1983. PMID 6139048. 
  44. ↑ "Identification of flumequine in a urinary calculus". Journal of Clinical Chemistry and Clinical Biochemistry. Zeitschrift Fur Klinische Chemie und Klinische Biochemie 25 (5): 313–314. May 1987. PMID 3612030. 
  45. ↑ "[Drug-induced urinary lithiasis]" (in fr). Presse Médicale 12 (38): 2389–2392. October 1983. PMID 6138768. 
  46. ↑ "Eight cases of quinolone allergy.". Revue Française d'Allergologie et d'Immunologie Clinique 37 (1): 15–19. January 1997. doi:10.1016/S0335-7457(97)80204-3. 
  47. ↑ Adverse Reaction Newsletter 1996:1 WHO collaborating centre for international drug monitoring
  48. ↑ "Central nervous system toxicity of quinolones: human and animal findings". The Journal of Antimicrobial Chemotherapy 26 (Suppl B): 219–225. October 1990. doi:10.1093/jac/26.suppl_b.219. PMID 2124211. 
  49. ↑ "[Acute psychiatric syndrome and quinolones]" (in fr). Journal de Toxicologie Clinique et Experimentale 10 (7–8): 469–472. 1990. PMID 2135062. 
  50. ↑ "[Neuropsychiatric manifestations and quinolones. Apropos of a case]" (in fr). L'Encephale 17 (6): 511–514. 1991. PMID 1666873. 
  51. ↑ "[Photophysical evaluation of photosensitization by various quinolones]" (in fr). Journal de Pharmacie de Belgique 45 (5): 299–305. 1990. PMID 1964964. 
  52. ↑ "[Photo-onycholysis caused by Apurone]" (in fr). Annales de Dermatologie et de Venereologie 110 (9): 765. 1983. PMID 6660786. 
  53. ↑ "The quinolone, flumequine, has no effect on theophylline pharmacokinetics". European Journal of Clinical Pharmacology 46 (5): 477–478. 1994. doi:10.1007/bf00191915. PMID 7957547. 
  54. ↑ "Flumequine(antiniotic antimicrobial agents) Manufacturers & Suppliers". 88chem.com. http://www.88chem.com/product-Antibiotic-and-Antimicrobial-Agents/10132/Flumequine-antiniotic-antimicrobial-agents-.html. 
  55. ↑ "Flumequine". Pymble, Australia: Australian Government Analytical Laboratories. http://www.fao.org/docrep/W8338E/w8338e0a.htm. 



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